Method of producing microscopic particles made of hydrolytically decomposable polymers and containing active substances

ABSTRACT

The invention concerns a method for the production of microscopic particles made of hydrolytically decomposable polymers, in particular copolymers, and containing active substances, using fluid gas with a uniform particle-size distribution and by the addition of biologically compatible amino acids. The microscopic particles produced by this method can be used as drugs for the treatment of humans or animals.

This invention relates to a method for manufacturing microparticlescontaining active substances from hydrolyrically decomposable polymers.

It has been known from numerous publications that resorbable polyesters,in particular those with a lactic acid base or glycolic acid base, andespecially their copolymers, are completely decomposed into endogenouscompounds in human or animal tissue or in human or animal fluids,wherein, depending on the purpose of use, the decomposition rates of thepolymers can be varied from a few hours up to several months.

The decomposition products reach the normal biochemical metabolism andare either directly excreted or finally metabolized into water andcarbon dioxide.

Of particular interest and importance are the applications of resorbentpolyesters in galenic preparations with delayed release of activesubstances for the manufacture of stock forms.

However, these kinds of polyesters can only then be used in human oranimal organisms, if they are free of impurities, which possibly maycause irritations. These impurities are, for example, nonconvertedresidual monomers, molecular weight regulators, or polymerizationcatalysts.

The present state of the art is represented in

Sustained release (drug) formulations, which are manufactured by usingthese types of resorbent polyesters that are suitable for subcutaneousinjections or implantations into the body, have been manufactured up tonow according to the following processes:

microencapsulation with organic solvents (L. M. Sanders et al., J.Contr. Release, 2 (1985) 187, or P. B. Deasy, Microencapsulation andRelated Drug Processes, M. Dekker Inc., New York 1984);

emulsification and subsequent solvent evaporation, T. R. Tice & R. M.Gilley, J. Contr. Release, 2 (1985) 343);

spray drying (D. L. Wise et al., Life Sci., 19 (1976) 867;

extrusion (A. J. Schwope et al., Life Sci., 17 (1975) 1877);

fusion embedding (A. J. Schwope et al., Life Sci., 17 (1975) 1877); or

boundary surface polymerization (G. Birrenbach & P. Speiser, J. Pharm.Sci., 65 (1976) 1763).

The above-mentioned processes either have the disadvantage of requiringlarge amounts of toxic organic solvents, wherein the resulting sustainedreleae (drug) formulations have high solvent residual concentrations inthe form of polymer embeddings (see, J. P. Benoit et al., Int. J.Pharmaceutics, 29 (1986) 95); or, the mentioned processes require hightemperatures or pressures, which, in particular, lead to high localizedtemperature increases and can damage the incorporated medicaments (seeL. M. Sanders et al., J. Pharm. Sci., 75 (1986) 356). If such amedicament type remains under the skin or in the tissue over an extendedperiod of time, toxic tissue reactions can be expected locally from theorganic solvents. Therefore, the solvent residues must be removed asthoroughly as possible from the mentioned products.

A detailed description of the above-mentioned manufacturing process ofthe present state of the art is found in DE-OS 37 44 329.

Finally, a process described as "Aerosol Solvent Extraction System"(ASES) for the manufacture of drug-containing microparticles loaded withactive substance is known from EP P 322 687 A2. In this process, activesubstance-loaded microparticles are manufactured with the aid of fluidgases. Microparticles are formed in a supercritical atmosphere from asolution of polymers and active substance, wherein the solvent isremoved by absorption into the gas phase.

Although this method is suitable for manufacturing auto-sterile activedrug-containing microparticles with a minimum of organic solvents (below10 ppm) without residual monomers, molecular weight regulators, orpolymerization catalyzers, it is, however, disadvantageous in that, withlarger batches, no reliable constant particle size distribution can beachieved and in that not all hydrolytically decomposable polymers can bereliably processed into microparticles.

Therefore, it is the object of this invention to manufacture activesubstance-containing microparticles with constant particle sizedistribution from hydrolyrically decomposable polymers, in particular,from copolymers of lactic acid and glycolic acid.

This object is achieved in accordance with the present invention inthat, each time at least one physiologically compatible amino acid of asolution of hydrolytically decomposable polymers or copolymers and of atleast one active substance in the corresponding solvents is added,microparticles are formed in a supercritical atmosphere, wherein thesolvents are removed by absorption in the gas phase.

In accordance with this invention, any active substance can be used.Examples of the active substances are medicaments, toxins, and viruses.We refer to U.S. Pat. No. 3,773,919 with respect to this concept.

All biologically compatible, hydrolyrically decomposable polymers andcopolymers can be used as carrier substances.

We would like to name the following:

Poly-1-lactide (1-PLA), poly-d,1-lactide (PLA),poly-1-lactide-coglycolides (1-PLGA), as well aspoly-d,1-lactide-coglycolides (PLGA) with variable portions of themonomers of lactic acid (PLA) and glycolic acid (GA). Preferably, thepolymer lactide-coglycolide comprises a molar ratio between 85:15 and50:50. In particular, the molar ratio 75:25 is preferred.

Amino acids which can be used in the invention, without restrictioninclude L-lysine, L-phenylalanine, L-tryptophane, and D,L-phenylalanine.

According to an embodiment of this invention, nitrous oxide, carbondioxide, halogenated hydrocarbons, saturated or unsaturatedhydrocarbons, dinitrogen dioxide (N₂ O₂), or ammonia, or mixturesthereof, can be used as fluid gases.

The invention will be better understood from the following descriptionthereof, taken in conjunction with accompanying FIG. 1, which shows aflow diagram of a process suitable for making the compositions of theinvention.

According to another embodiment of the invention, correspondingly suitedgases, as well as the low-boiling liquids and mixtures thereof, whichare convertible into a supercritical condition, can each be used as afluid gas.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention.

EXAMPLE 1

Manufacture of Microparticles Containing Buserelin Polymer: poly-(D,L)lactide coglycolide, i.v. 0.8 dl/g

0.375 g L-lysine (Aldrich) is dissolved in 25 ml glacial acetic acid(Merck); 2.5 g poly-(D,L)lactide coglycolide (monomer ratio 75:25) isdissolved in 75 ml dichloromethane (Merck), Both solutions are united,Then, 0.06 g buserelin is added and stirred, until a clear solution isobtained: 0.06% solution, with reference to buserelin.

This solution is placed in a reservoir 17 (FIG. 1), and fed to a pistonstroke pump 16 though line 50. From pump 16, the solution passes throughline 52, heat exchanger 15, line 54, valve 20, and line 55, to nozzle118. At an excess pressure of 94-96 bar, the solution containingbuserelin and the copolymer is atomized through a conventionalmonocomponent nozzle 118, type Schlick 121 V, in tower 12, wherein theCO₂, in supercritical condition, at 90 bar/36° C. and a flow rate of 8.9kg/h, is fed in a parallel flow, via inlet 8, through the tower. Nozzle118 has a diameter of 0.5 mm, and the spray angle is 10°.

In accordance with the high affinity of the supercritical CO₂ for thesolvent, solvent is withdrawn from the primarily formed droplets;spherical solid solutions remain. The CO₂ loaded with the solvent leavesthe tower end through lines 42 and 40 controlled by two magnet valves 7and 9 and is relieved to 60 bar. The valves are operated to permit theamount of the fluid gas entering the tower per unit time to escape whilemaintaining the operating pressure of the tower.

The CO₂, loaded with solvent which is at a pressure of 60 bar due to thepressure relief, is fed through line 62 to separator 10, which has beenheated to 21° C., wherein the solvent mixture separates as a consequenceof the severely reduced solubility in the CO₂ under these conditions.The CO₂, which has been freed from the solvent mixture, is again heatedand pressurized to a supercritical condition (90 bar, 36° C.) throughlines 64 and 32, and is fed again, for further drying of the formedparticles, to tower 12 through inlet 8, via line 34, pump 4, line 36,heat exchanger 5, and line 38.

Removal of the solvent mixture in separator 10 takes place, after theseparation of the separator 10 from the circuit, through valves 6 and 13and relief to atmospheric pressure.

After the completion of the actual spraying, which amounts to about 20to 50 minutes, the CO₂ is fed through the tower until no solvent can bereclaimed any longer in separator 10.

After completion of the drying process, the CO₂ flow to tower 12 is shutoff, the tower is relieved to atmospheric pressure via valves 11 and 14,and the particles are removed at the lower tower end 19.

The dry powder, which is removed from the tower, consists of spherescontaining buserelin and having a diameter of 5 to 10 μm.

EXAMPLE 2

Manufacture of Microparticles Containing LH-RH-Antagonist Polymer:Poly-(D,L) lactide coglycolide, i.V. 0.8 dl/g

The manufacture takes place following the method of Example 1.

0.375 g L-lysine (Aldrich), 0.06 g LH-RH-Antagonist, 2.5 gpoly(D,L-)lactide coglycolide (75:25) i.V. 0.8 dl/g are dissolvedtogether with 25 ml glacial acetic acid (Merck) and 75 mldichloromethane (Merck) and stirred until a clear solution is obtained.

This solution is sprayed at 94-96 bar excess pressure in the tower ofthe high pressure unit. CO₂ at 90 bar/36° C. is fed in parallel flowthrough the tower. The CO₂ flow rate amounts to 8.9 kg/h. A conventionalmono-component nozzle of the Schlick 121 V type serves as a nozzle,having a nozzle diameter of 0.5 mm and a spray angle of 10°.

After completion of the actual spray time, the CO₂ is fed through thetower until no solvent is reclaimed in the separator of the highpressure unit.

The dry powder obtained from the tower consists of spheres with adiameter of 5-10 μm.

EXAMPLE 3

Manufacture of Microparticles Which Do Not Contain an Active Substance

The manufacture takes place following the method of Example 1.

A solution of 2.5 g poly-(D,L)lactide coglycolide, 75:25 i.V 0.8 dl/g in75 ml dichloromethane and 25 ml glacial acetic acid (all Merck), whichcontains 0.375 g L-lysine (Aldrich), is atomized at about 94-96 barexcess pressure in the tower of the high pressure unit. Simultaneously,the CO₂ is fed at 90 bar/36° C. in parallel flow through the tower. TheCO₂ flow rate amounts to 8.9 kg/h. A conventional mono-component nozzleof the Schlick type 121 V with a diameter of 0.5 μm and a spray angle of10° serves as a nozzle.

After completion of the actual spray time, the CO₂ is fed through thetower until no solvent is reclaimed in the separator of the highpressure unit.

The dry powder obtained from the tower consists of spheres with adiameter of 5-10 μm.

Table I summarizes further examples of polymers useful for themanufacture of microparticles containing active substances in accordancewith the invention.

The manufacture of those microparticles takes place following theprocedure of Examples 1 to 3.

The microparticles, which were thus obtained, are sterile and free ofresidual solvents, polymerization catalyzers, or initiator molecules.

They have a constant particle size distribution of 5 to 10 μm.

Therefore, they can be used as a sustained-release drug formulation typefor subcutaneous injections or implantations in the body.

                                      TABLE 1                                     __________________________________________________________________________                 Inherent                      Amino                                           Viscosity                                                                          Molar Ratio                                                                            Polymer                                                                            Active Substance                                                                         Acid                               No.                                                                              Polymer   dl/g Lactide:Glycolide                                                                      (g)  (g)                                                                              Amino Acid                                                                            (g)                                __________________________________________________________________________    1  Poly-(D,L)-lactide                                                                      0.3           2.0  0.06                                                                             L-Lysine                                                                              0.5                                2  Poly-(D,L)-lactide-                                                                     0.8  75:25    1.0  0.03                                                                             L-Phenyl-                                                                             0.25                                  coglycolide                     alamine                                    3  Poly-(D,L)-lactide-                                                                     0.8  75:25    2.0  0.06                                                                             D,L-Phenyl-                                                                           0.5                                   coglycolide                     alamine                                    4  Poly-(D,L)-lactide-                                                                     0.8  75:25    2.2  0.06                                                                             L-Tryptophane                                                                         0.55                                  coglycolide                                                                5  Poly-L-lactide                                                                          0.56          6.0  0.18                                                                             L-Lysine                                                                              0.9                                6  Poly-L-lactide                                                                          1.0           3.0  0.10                                                                             L-Lysine                                                                              0.45                               __________________________________________________________________________     The polymers are dissolved each time in 75 ml dichloromethane (Merck) and     25 ml glacial acetic acid.                                                    The respective amount of amino acid is added. D,Lphenylalanine is to be       predissolved suitable in up to 50 ml of ethanol (Merck).                 

The foregoing detailed description has been given for clearness ofunderstanding only, and no unnecessary limitations should be understoodtherefrom, as modifications will be obvious to those skilled in the art.

What is claimed is:
 1. A process for the manufacture ofsustained-release microparticles containing an active substancecomprising the steps of(a) preparing a solution of a hydrolyricallydecomposable polymer in a solvent; (b) dissolving or dispersing at leastone active substance and at least one free amino acid in said solution;(c) atomizing or spraying the dispersion or solution produced in step(b) while simultaneously adding a fluid gas at supercritical conditions,thereby extracting said solvent from said dispersion or solution intosaid fluid gas, leaving microparticles containing active substance andpolymer; (d) separating said fluid gas from said microparticles; and (e)recovering said microparticles.
 2. A process according to claim 1wherein said polymer is a copolymer.
 3. A process according to claim 1wherein said polymer is selected from the group consisting ofpoly-1-lactide, poly-d,l-lactide or poly-1-lactide-coglycolides, andpoly-d,l-lactide-coglycolides with variable portions of the respectivemonomer components.
 4. A process according to claim 1 wherein saidpolymer lactide-coglycolide has a molar ratio between 85:15 and 50:15.5. A process according to claim 1 wherein said amino acid is L-lysine,L-phenylalanine, or L-tryptophane.
 6. A process in accordance with claim1 wherein said amino acid is D,L-phenylalanine.
 7. A process inaccordance with claim 1 wherein said fluid gas is selected from thegroup consisting of dinitrogen oxide, carbon dioxide, halogenatedhydrocarbons, saturated or unsaturated hydrocarbons, ammonia, andmixtures thereof.
 8. A process according to claim 1 wherein said fluidgas is selected from the group consisting of gases and low boilingliquids, and mixtures thereof, which can exist in a supercriticalcondition.